This is a resubmission of our initial application. Alterations of serotonin (5-HT) and dopamine (DA) activity may contribute to extremes of appetitive behaviors in anorexia nervosa (AN) and bulimia nervosa (BN), through effects on inhibitory and reward neural pathways. In order to avoid the confounding effects of malnutrition, and because they have behaviors and neural circuit alterations relevant for this study, we will study 25 recovered (REC) restricting-type AN, 25 REC bulimic-type AN (AN-BN), 25 REC BN, and 25 control women (CW). This 5 year study, of women 18 to 45 years old, will employ positron emission tomography (PET) imaging with radioligands for the serotonin (5-HT) transporter ([11C]DASB) and dopamine (DA) D2/D3 receptors ([11C]raclopride). In Aim 1, we predict that REC AN will have elevated, and REC BN will have diminished [11C]DASB binding potential (BP) in midbrain and striatal regions. Differences of 5-HT activity may shed light on how AN have extraordinary self-control of appetitive behaviors, consistent with fMRI studies suggesting enhanced neural inhibitory processes. In contrast, BN individuals may be vulnerable to overeating when they are hungry, because they have less ability to self-regulate and control their impulses. Individuals with AN and BN may share a DA-related ventral limbic system alteration, making them vulnerable to being unable to appropriately response to the rewarding aspects of appetitive stimuli. In Aim 2, we predict that REC AN and BN will have increased [11C]raclopride BP in the anterior ventral striatum (AVS). Our preliminary data supports emerging concepts suggesting that 5-HT and DA interactions contribute to a balance between (respectively) an aversive or inhibitory system, and a reward or motivational system. In Aim 3, we seek to replicate preliminary data showing that striatal [11C]raclopride and [11C]DASB binding may help to explain the neurobiology responsible for an elevated harm avoidance (a measure of anxiety and inhibition) trait in ED. Our overarching goal is to use multi-modal brain imaging to characterize neural processes in AN and BN and their relationship to behavior. Aim 4 will integrate PET findings with data from a previously funded application (using the same subjects) in which fMRI characterizes how an anterior insula and striatal network contributes to the sensory- interoceptive-hedonic-motivational aspects of feeding behavior. Our data suggest the BOLD response of this network to tastes of sucrose is diminished in REC AN and is negatively associated with ventral putamen [11C]raclopride BP. Thus, REC AN with the least sensory-interoceptive response to sucrose may have the most diminished striatal DA concentrations, and presumably less motivation to eat. Aim 5 will collect DNA to explore the relationship between genetic alterations, PETand fMRI measures of neural circuitry function. Effective treatments for AN and BN have been elusive, and there is little understanding of puzzling symptoms such as extremes of eating behaviors. A better understanding of the neurobiology is important for developing specific and more powerful therapies for these often chronic and deadly disorders. PUBLIC HEALTH RELEVANCE: Evidence suggests that the regulation of the neurotransmitters serotonin and dopamine is altered in the brain of people with anorexia nervosa (AN) and bulimia nervosa (BN). This study will use brain imaging technologies (positron emission tomography [PET] and functional magnetic resonance imaging [fMRI]) to measure specific components of serotonergic and dopaminergic neurocircuits and to investigate how those circuits modulate appetitive neural circuitry when responding to the taste of sugar, which might explain why AN are able to starve themselves and become emaciated, while BN periodically overeat. This application will help to understand the unique puzzling symptoms in AN and BN and contribute to finding better methods for identifying effective medications in these often relapsing and sometimes chronic disorders.